Electrolytic CIP-Cleaning Process for Removing Impurities from the Inner Surface of a Metallic Container

ABSTRACT

The invention relates to a novel electrolytic process for removing impurities from the inner surface of a metallic container. The process is particularly useful for cleaning process reactors used for culturing microorganisms, and storage tanks used for storing metabolites formed in the process reactor, as well as containers for dairy products.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/778,940, filed Feb. 27, 2013, which is a continuation of U.S.application Ser. No. 13/109,518, filed May 17, 2011 (now abandoned),which is a continuation of U.S. application Ser. No. 12/872,516, filedAug. 31, 2010 (now abandoned), which is a continuation of U.S.application Ser. No. 12/728,905, filed Mar. 22, 2010 (now abandoned),which is a continuation of U.S. application Ser. No. 12/529,639, filedSep. 2, 2009 (now abandoned), which is a 35 U.S.C. §371 national stageapplication of International Patent Application PCT/EP2008/052971(published as WO 2008/110587 A1), filed Mar. 13, 2008, which claimedpriority of European Patent Application 07104036.4, filed Mar. 13, 2007;this application further claims priority under 35 U.S.C. §119 of U.S.Provisional Application 60/918,335, filed Mar. 16, 2007; the contents ofall above-named applications are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to a novel electrolytic process for removingimpurities from the inner surface of a metallic container. The processis particularly useful for cleaning process reactors used for culturingmicroorganisms, and storage tanks used for storing metabolites formed inthe process reactor, as well as containers for dairy products.

BACKGROUND OF THE INVENTION

For industrial scale processes, e.g. for culturing microorganisms andcells and for handling, processing and purifying biological materials,e.g. microorganisms, cells, polypeptides, proteins, DNA, RNA,lipoproteins, lipids (steroids, terpenes, waxes and fatty acids),high-molecular carbonhydrates and the like, it has proven to beparticularly difficult to completely remove all traces of material onnano-scale from the inner surface of the container(s) which have beeninvolved in such processes.

It turns out that biological materials, e.g. proteins, strongly adhereto metal surfaces, e.g. stainless steel surfaces, and that a monolayerof high molecular weight compounds or biological materials, e.g.proteins, can be extremely difficult to completely remove withoutcostly, energy demanding and time-consuming cleaning processes, whichfurther may cause environmental problems.

Residues of proteins that are partly degraded are potentiallyimmunogenic. Residues of proteins may act as nuclei (seeds) fordenaturation of proteins during a subsequent manufacturing campaign. Toavoid cross-contamination when tanks are used to produce differentproteins and protein products, it is essential that the inner surface ofthe container is clean at a nano-scale level.

U.S. Pat. No. 7,090,753 B1 discloses an electrolytic cell which canproduce charged water having excellent performance of improving surfacecleaning or treatment.

KR 1082761 A discloses a method for grinding the inner walls of a drugtank in order to maintain the degree of purity of stored drugs byminimizing the gush of metal components from the inner walls of the drugtank. In the process, the inner wall is i.a. grinded by an electrolyticsolution, and subsequently an oxide membrane is formed by reacting thesurface with 20% nitric acid solution. It is stated that the use of highpurity detergents can be reduced and that the cleaning time can beshortened.

However, there is still a need for cost- and time efficient processesfor cleaning the surface of containers of the above-mentioned type on anano-scale, in particular such methods which due to their simplicity areenvironmentally acceptable.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides an electrolytic process for removingimpurities, e.g. contaminants and residues, in particular impuritiesconsisting of biological materials, from the inner surface of a metalliccontainer (5), said process comprising the step of

a) establishing an electrical circuit comprising (a) the wall of thecontainer as a first electrode (1), (b) a second electrode (2), and (c)an electrolyte solution (3) forming electrical connection between saidfirst electrode and said second electrode, the connection between thefirst electrode and the electrolyte solution defining a contact area(4); and

b) facilitating that said contact area (4) is moved across at least asubstantial part of said inner surface so as to allow said electrolytesolution (3) to contact said inner surface to be depleted of theimpurities, and simultaneously applying a predetermined current densityat said contact area (4).

The process has to the best of the inventors' knowledge never been usedbefore for “clean in place” (CIP)-cleaning of the inner surface ofcontainers (e.g. production or storage tanks or pipes for medicalproduction).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a process reactor (reaction vessel) (5) having a wall(1) used as the anode, and having arranged therein a rotable tubularmember (2) for facilitating flow of the electrolyte solution (3)provided via a pump (not shown). The tubular member is also used as thecathode (as shown) or can have a cathode arranged therein (alternativeembodiment). Upon rotation and up-and-down movement of the tubularmember, the contact area (4) is moved across a substantial part of theinner surface.

FIG. 2 illustrates a process reactor (reaction vessel) (5) having a wall(1) used as the anode, and having arranged therein a rotable member (2)for facilitating flow of the electrolyte solution (3) provided via apump (not shown). The tubular member is moved close to the inner walland has a slit which allows the electrolyte solution to exit the tubularmember. The tubular member is also used as the cathode (as shown) or canhave a cathode arranged therein (alternative embodiment). Upon rotationof the tubular member around the axis (show with a dashed line), theelongated contact area (4) is moved across a substantial part of theinner surface.

FIG. 3 illustrates various embodiments of the cross-section of thetubular member illustrated in FIG. 2.

FIGS. 4 and 5 illustrate the arrangement of a rotable spraying devicewithin a process reactor. After having served to establish electricalconnection between the spraying device (second electrode; cathode inFIG. 4 and anode in FIG. 5) and the inner wall of the container (firstelectrode; anode in FIG. 4 and cathode in FIG. 5), the electrolytesolution is collected in the lower part of the container and is pumpedback through the rotable spraying device via the pump. It is noted thatthe spraying device provides several streams (3′) collectivelyrepresenting the electrolyte solution (3), and that the “contact area”(4) is a collection of a number of individual contact areas (4′).

FIG. 6 illustrates a Pourbaix-diagram demonstrating the possible area ofpassivation.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the present invention provides an electrolyticprocess of removing impurities from the inner surface of containers,i.e. containers having an inner surface of a metallic material, such asstainless steel, titanium, tantalum or niobium. Containers of stainlesssteel are of particular importance.

Containers for which the present process is particularly relevant arereactors for culturing microorganisms and cells and for storing,handling, processing and purifying biological material, e.g.microorganisms, cells, polypeptides, proteins, DNA, RNA, lipoproteins,lipids (steroids, terpenes, waxes and fatty acids), high-molecularcarbonhydrates and the like. Hence, in the present context, the term“container” encompasses process reactors, tubes, pipes, storage tanks,etc. Containers for handling diary products are also highly relevant.

It is understood that the process of the invention is particularlyrelevant for industrial scale equipment; hence the container preferablyhas a volume of at least 10 L, such as at least 100 L, or even at least1,000 L.

The invention resides in the finding that electrolytic cleaning of theinner surface of a metallic surface of a container can be obtained byapplication of a high current density by means of an electrical circuitcomprising (a) the wall of the container as a first electrode (1), (b) asecond electrode (2), and (c) an electrolyte solution (3) formingelectrical connection between said first electrode and said secondelectrode, wherein the connection between the first electrode and theelectrolyte solution defines a contact area (4). Means are includedwhich facilitate that the contact area can be moved across at least asubstantial part of the metallic inner surface of the container, while apredetermined current density is simultaneously applied at said contactarea (4), i.e. the electrolytic process is effectuated over asubstantial part of the inner surface.

In the most typically embodiments, the current density is in the range1-60 A/dm², e.g. in the range of 1-30 A/dm², such as 3-20 A/dm².

It should be understood that the contact area at any time of the processonly represents a fraction of the total area to be treated. Hence,preferably, the ratio between (i) the total area of the part of theinner surface which the contact area is moved across and (ii) thecontact area is at least 10:1, such as at least 20:1, or even at least50:1.

It should be understood that the contact area in question may be the sumof a number of individual contact areas, e.g. as illustrated in FIGS. 4and 5.

Upon application of a high current density between the first electrodeand the second electrode (one of which being the anode and the otherbeing the cathode) having an aqueous electrolyte solution there between,hydrogen gas will be formed at the cathode and oxygen gas will be formedat the anode.

The chemical reactions involved are:

Anode reaction: 2H₂O→O₂+4H⁺+4e ⁻

Cathode reaction: 2H₂O+2e ⁻→H₂+2OH⁻

Under the real cleaning process, the surface chemistry gets veryalkaline at the cathode and in that way acts as the builder chemistry inconventional cleaning chemistry.

The rational behind the invention is that the high cathodic currentdensity applied to the metallic surface, e.g. a stainless steel surface,will result in the formation of hydrogen bubbles at the inner surface ofthe container, and that any material which adheres to the surfacethereby will be removed under the influence of the formed hydrogen andhydroxyl ions. Furthermore, the electrochemical interaction with theimmobilized organic impurities at the surface will be destroyed therebyleaving the surface cleaned upon molecular or nano-scale. This isillustrated in Example 2.

The process according to the invention cleans the inner surface usingonly electricity and an electrolyte solution. The electrolyte solutionneeds in principle only to contain very dilute amounts of non-toxicchemicals, such as alkali-metal hydroxides, such as NaOH and KOH, or aneutral salt, such as Na₂SO₄ or K₂SO₄, in purified water. Forenvironmental reasons, and for reasons of disposal, the electrolytesolution is preferably a solution of one or more components selectedfrom the group consisting of sodium hydroxide, potassium hydroxide,sodium sulphate and potassium sulphate.

The ionic strength of the electrolyte solution is typically in the range0.05-2.0 N, such as 0.1-1.0 N.

Moreover, the electrolyte solution may in some interesting embodimentadditionally comprise one or more complexing agent, such as one or moreselected from gluconates, EDTA, and hydroxyl carboxylic acid (e.g.citric acid).

On the other hand, and contrary to conventional methods for cleaningprocess reactors which utilizes various types of detergents, theelectrolyte solution is preferably essentially free of detergents.

Apart from the requirement of a sufficient current density, the contacttime should preferably be sufficiently long so as to allow for anefficient removal of the impurities. The movement of the secondelectrode relative to the inner surface of the container will determinethe period at which an incremental area of the inner surface is exposedto the applied current. Hence, typically, the movement of the contactarea is such that the contact time of the contact area is at least 1second.

The equipment used for facilitating the movement of the contact areaacross the inner surface (or at least a part thereof), may includemotors, e.g. stepper motors, as well as robots. Further, the movementmay—although not particularly preferred—be effected manually.

The electrical circuit comprises the first electrode, the secondelectrode and the electrolyte solution.

In one embodiment, the first electrode is the cathode and the secondelectrode is the anode. In this embodiment, hydrogen gas is formed atthe inner surface of the container.

In another embodiment, the first electrode is the anode and the secondelectrode is the cathode. In this embodiment, oxygen gas is formed atthe inner surface of the container.

That constellation makes it also possible—in a special embodiment—topassivate the stainless steel surface as a post treatment after theelectrolytic CIP-cleaning, where the first electrode is used as acathode.

Under the passivation process, the first electrode act as the anode andthat makes it possible to form a passivating layer consisting of oxides,i.e. a treatment very similarly to the passivation in nitric acid. ThePourbaix-diagram of FIG. 6 indicates the possible area for passivation.

The anodic current density which is necessary to render the processeffective is typically at least 1 A/dm² corresponding to a potential(SHE) between +400 mV and +1500 mV. For practical reasons, the currentdensity is typically in the range 1-60 A/dm², e.g. in the range of 1-30A/dm².

In one particularly interesting embodiment, the second electrode is atubular member facilitating a flow of the electrolyte solution. Thetubular member may be designed as a low pressure spray nozzle to ensurea coherent beam of the electrolyte, which form a linear contact areawith some extent. Alternatively, the electrode is placed in the waterbeam formed by a spray nozzle. This embodiment corresponds to the oneillustrated in FIG. 1.

In another interesting embodiment, the electrolyte solution is fed tothe gap between the first electrode and the second electrode by means ofa tubular member having a slit. This embodiment corresponds to the oneillustrated in FIG. 2. In this embodiment the residence time of theelectrolyte solution may be increased by arranging a porous structure inthe before-mentioned gap.

In a further variant, the electrolytic process is carried out within ajet beam between the area to be cleaned (the first electrode; a cathode)and a cleaning nozzle. An anode is inserted into the tank in appropriatedistance allowing a non-interrupted and coherent beam of electrolyte toconnect to the anode and cathode (tank wall). The beam is moved to coverthe whole area of the tank. Within this embodiment, the flow of theelectrolyte solution is preferably predominantly laminar.

In an alternative embodiment, the electrolyte solution which formselectrical communication between said first electrode and said secondelectrode is held in a porous structure, e.g. in a sponge or a brush.Such a porous structure may be moved across the inner surface mymechanical means, e.g. by a motor/motors or a robot.

In one particularly preferred embodiment, the process according toinvention comprising the step of:

a) establishing an electrical circuit comprising (a) the wall of thecontainer as the anode (1), (b) a cathode (2), and (c) an electrolytesolution (3) of one or more components selected from the groupconsisting of sodium hydroxide, potassium hydroxide, sodium sulphate andpotassium sulphate, optionally further comprising a complexing agent,said electrolyte solution forming electrical connection between saidanode and said cathode, the connection between the first electrode andthe electrolyte solution defining a contact area (4); and

b) facilitating that said contact area (4) is moved across at least asubstantial part of said inner surface so as to allow said electrolytesolution (3) to contact said inner surface to be depleted of theimpurities, and simultaneously applying a current density in the range1-60 A/dm²,

wherein the ratio between (i) the total area of the part of the innersurface which the contact area is moved across and (ii) the contact areais at least 50:1, and

wherein the movement of the contact area is such that the contact timeof the contact area is at least 1 second.

The cleanness of the surfaces treated according to the process accordingto the present invention can be verified via XPS (X-ray photonSpectroscopy), e.g. as described in the Examples section.

The process of removing impurities as defined herein is believed toreduce the cleaning cycle of the equipment significantly; as compared toconventional CIP cleaning and will “re-set” the surface. This isillustrated by the results presented in the examples section which showsthat X-ray photon spectroscopy measurements of a pristine stainlesssteel surface and a stainless steel surface treated in accordance withthe process of the invention appear to be essentially the same.

The process according to the invention can suitably be used for cleaningprocess reactors being contaminated with a variety of organicconstituent, e.g. proteins, milk, etc., and the use is therefore notrestricted to the drug industry.

EXAMPLES XPS (X-Ray Photon Spectroscopy)

XPS is a versatile technique for analyzing the top ˜10 nm of a surface,providing information on the elements present at the surface and thechemical state they are in.

Example 1

Table 1 shows the XPS measurement of a pristine surface of stainlesssteel type 316. The surface is seen to consist of oxides of mainlychromium and less amounts of iron oxide.

TABLE 1 Element (Atomic %) Specimen C 1s O 1s Cr 2p Fe 2p Pristinestainless 38.1 48.4 11.3 2.2 steel XPS average values of the referencesurface. All results are in atomic %

Example 2

In Table 2, below, the elemental compositions of surfaces afterimmersion in insulin solution and additional various cleaning processesare given. The presence of nitrogen and sulfur along with the increasedcarbon signal show that insulin is still present at the surface aftercleaning by water immersion, water spray and conventional CIP detergent(CIP 100 supplied by Steris, UK), while a surface that is practicallyidentical to the pristine surface is obtained after conducting theprocess in accordance with the present invention.

TABLE 2 Element (Atomic %) Cleaning process C 1s O 1s Cr 2p Fe 2p N 1s S2p Pristine stainless 38.1 48.4 11.3 2.2 — — steel Immersion in 50.332.9 5.2 1.2 9.3 0.8 water Water spray 49.3 35.6 6.5 1.6 6.6 — After CIP100 54.3 31.9 6.8 1.4 5.3 0.4 detergent Process according 35.8 48.2 12.53.4 — — to the invention XPS average values of surface after immersionin insulin and additional cleaning processes. All results are in atomic%

1. A medical delivery system comprising: a) a container adapted tocontain a medicament in a reservoir and to contain a slideably arrangedpiston which is moveable along a first axis in a distal directiontowards an outlet of the reservoir so as to reduce the volume of thereservoir and expel the medicament through the outlet, the containerfurther comprising a first protrusion, the location of the firstprotrusion representing at least one parameter associated with thecontainer; b) a dosing assembly adapted to be secured to the containerso as to allow driving means of the dosing assembly to move the pistonof the container in the distal direction, the dosing assembly furtherhaving electric circuitry configured for identifying the location of thefirst protrusion on the container, wherein the medical delivery systemcomprises a first electric resistive track disposed in the dosingassembly, and, in use, a first wiper slideably engaging said firstelectric resistive track, the first wiper being associated with saidfirst protrusion when the container is secured to the dosing assembly,the first electric resistive track and the first wiper being coupled tothe electric circuitry so as to detect the relative position of thefirst wiper with respect to the first electric resistive track tothereby identify said container.
 2. The medical delivery systemaccording to claim 1, wherein the dosing assembly comprises a firstswitch element which is adapted to cooperate with a second protrusiondisposed on the container, the first switch element and the electriccircuitry being adapted to detect when the container is correctlysecured to the dosing assembly.
 3. The medical delivery system accordingto claim 2, wherein the dosing assembly comprises a second switchelement which is adapted to cooperate with said second protrusiondisposed on the container, the second switch element being adapted toactivate a controller of said electric circuitry responsive to initialcoupling of the container to the dosing assembly.
 4. The medicaldelivery system according to claim 1, wherein the medical deliverysystem comprises a second electric resistive track disposed in thedosing assembly, and a second wiper slideably engaging said secondelectric resistive track, and wherein the container comprises a thirdprotrusion, the second wiper being associated with the third protrusionwhen the container is secured to the dosing assembly.
 5. The medicaldelivery system according to claim 1, wherein the container has aproximal end adapted to be at least partly received in the dosingassembly and wherein at least one of said protrusions is/are arranged onthe proximal end of the container extending in the proximal direction.6. The medical delivery system according to claim 1, wherein thecontainer has a generally cylindrical section and wherein at least oneof the protrusions are arranged on the external face of the cylindricalsection.
 7. The medical delivery system according to claim 1, whereinthe electric resistive track is a thin film potentiometer or a thickfilm potentiometer.
 8. The medical delivery system according to claim 1,wherein at least one of said wipers are spaced away from its respectiveelectric resistive track when the container is spaced away from thedosing assembly.
 9. The medical delivery system according to claim 1,wherein the first and/or the third protrusion of the container functionsas said wiper(s), when the container is secured in the dosing assembly.10. The medical delivery system according to claim 1, wherein thecontainer comprises first fastening means releasably coupleable tosecond fastening means of the dosing assembly by a sequence of movementscomprising a relative axial movement along a first axis followed by arelative rotational movement around the first axis.
 11. The medicaldelivery system according to claim 1, wherein the container comprisesfirst fastening means releasably coupleable to second fastening means ofthe dosing assembly by a purely axial movement along the first axis andwhere the dosing assembly comprises means for rotational aligning thecontainer with the dosing assembly.
 12. The medical delivery systemaccording to claim 10, wherein the first and the second fastening meansare configured to allow the container to be secured to the dosingassembly in a single predefined rotational orientation with respect tothe dosing assembly.
 13. The medical delivery system according to claim10, wherein the first and the second fastening means are configured toallow the container to be secured to the dosing assembly in twopredefined rotational orientations with respect to the dosing assembly,the two rotational orientations being opposed by 180 degrees.
 14. Acontainer for use in the medical delivery system accordingly to claim 2,the container being adapted to contain a medicament in a reservoir andto contain a slideably arranged piston which is moveable along a firstaxis in a distal direction towards an outlet of the reservoir so as toreduce the volume of the reservoir and expel the medicament through theoutlet, the container further comprising a proximal end having a cavityadapted to receive driving means of the dosing assembly, the proximalend including a portion having a circular cross-section, wherein firstand a second protrusions and optionally additional protrusion(s) arelocated along the periphery of the circular section of the container andextends in the proximal direction, and wherein for at least one of saidprotrusions, the centre-to-centre spacing between said at least oneprotrusion and each of its neighboring protrusions are non-equidistant.15. The container according to claim 14, wherein the container comprisesfirst fastening means for securing the container to second fasteningmeans of the dosing assembly, the first fastening means comprising tworadially extending male members.
 16. The container according to claim14, wherein at least one of said protrusions have a peripheral widthalong the periphery of the circular section corresponding to less than45 degrees, preferably less than 30 degrees, more preferably less than20 degrees.